Recent insights into the genetics of inflammatory bowel disease.

Abstract

Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.

Features of disease-associated genetic variation. Most cases of inflammatory bowel disease (IBD) are multifactorial in etiology, reflecting the effects of multiple genetic risk alleles and developmental and environmental factors. Rare cases of early-onset IBD, with extreme phenotypes, might be single-gene, Mendelian disorders (eg, autosomal recessive mutations in IL10RA or ILRB)—extremely rare mutations with strong effects. In contrast, most of the alleles identified by genome-wide association studies are relatively common (allele frequencies >5%), with modest or low effects and odds ratios <1.5. Greater effects (intermediate to high) include the relatively low-frequency risk alleles in NOD2 and the variant that encodes Arg381Gln in IL23R. Among complex disorders, it is unusual to have common alleles that have strong effects; an exception is that some alleles of the gene that encodes complement factor H confer high-risk for age-related macular degeneration (AMD).

Interleukin (IL)-23 vs IL-12 signaling. IL-23 and IL-12 signaling are mediated by binding of the cytokine heterodimer to a heterodimeric receptor. These pathways share components of the cytokine (IL12B, p40), receptor (IL12RB1), and downstream signaling components (JAK2 and TYK2). Activation and phosphorylation of downstream components result in the recruitment and activation of signal transducer and activator of transcription (STAT) proteins (STAT3 in IL-23 signaling, STAT4 in IL-12 signaling), which subsequently translocate to the nucleus to activate transcription. Inflammatory bowel disease (IBD) and psoriasis (PS) are each associated with variants in IL23R, IL12B (p40) and TYK2. IBD, PS, and ankylosing spondylitis (AS) are all associated with the chromosome 1p31 region that includes the C-terminal 7 exons of IL23R, and extends into the intergenic region between IL23R and IL12RB2. In contrast, Behçet's disease (BD) and primary biliary cirrhosis (PBC) are associated with the inter-genic region, between IL23R and IL12RB2.